Autophagy Defect Is Associated with Low Glucose-Induced Apoptosis in 661W Photoreceptor Cells

Abstract

Glucose is an important metabolic substrate of the retina and diabetic patients have to maintain a strict normoglycemia to avoid diabetes secondary effects, including cardiovascular disease, nephropathy, neuropathy and retinopathy. Others and we recently demonstrated the potential role of hypoglycemia in diabetic retinopathy. We showed acute hypoglycemia to induce retinal cell death both in vivo during an hyperinsulinemic/hypoglycemic clamp and in vitro in 661W photoreceptor cells cultured at low glucose concentration. In the present study, we showed low glucose to induce a decrease of BCL2 and BCL-XL anti-apoptotic proteins expression, leading to an increase of free pro-apoptotic BAX. In parallel, we showed that, in retinal cells, low glucose-induced apoptosis is involved in the process of autophagosomes formation through the AMPK/RAPTOR/mTOR pathway. Moreover, the decrease of LAMP2a expression led to a defect in the autophagosome/lysosome fusion process. Specific inhibition of autophagy, either by 3-methyladenine or by down-regulation of ATG5 or ATG7 proteins expression, increased caspase 3 activation and 661W cell death. We show that low glucose modifies the delicate equilibrium between apoptosis and autophagy. Cells struggled against low nutrient condition-induced apoptosis by starting an autophagic process, which led to cell death when inhibited. We conclude that autophagy defect is associated with low glucose-induced 661W cells death that could play a role in diabetic retinopathy. These results could modify the way of addressing negative effects of hypoglycemia. Short-term modulation of autophagy could be envisioned to treat diabetic patients in order to avoid secondary complications of the disease.

Activation of Autophagic Flux against Xenoestrogen Bisphenol-A-induced Hippocampal Neurodegeneration via AMP kinase (AMPK)/Mammalian Target of Rapamycin (mTOR) Pathways

“…Thus, we demonstrated that impaired autophagic flux by BPA enhances apoptosis by elevating the levels of cleaved caspase-3. Several studies report that autophagy impairment increases caspase-3 activity and cell death (72,92). Interestingly, long term exposure of BPA caused hippocampal neurodegeneration and reduced learning and memory ability in the rats.…”

Effect of autophagy inhibition on cell viability and cell cycle progression in MDA-MB-231 human breast cancer cells

“…This implies the effect of Atg7 deficiency on the cell cycle may associate with glucose starvation. The data supports a study by Balmer et al (19) which indicated that low glucose-induced apoptosis with inhibition of autophagy may lead to cell death in 661W photoreceptor cells. Ramírez-Peinado et al (20) hypothesized that autophagic flux induced by other stimuli is inhibited in the absence of glucose.…”

Autophagy: A Role in the Apoptosis, Survival, Inflammation, and Development of the Retina

“…In retinal cells, low glucose-induced apoptosis is involved in autophagosome formation through the AMPK/ RAPTOR/mTOR pathway [88]. The specific inhibition of autophagy, either by 3-MA or the downregulation of ATG5 or ATG7 protein expression, increased caspase 3 activation and induced 661W cell death.…”

“…The specific inhibition of autophagy, either by 3-MA or the downregulation of ATG5 or ATG7 protein expression, increased caspase 3 activation and induced 661W cell death. These results suggest that cells struggle against low nutrient-induced apoptosis by initiating an autophagic process but failed to survive when autophagy is inhibited [88]. In murine cytomegalovirus-induced retinal apoptosis, autophagy induced by rapamycin inhibited apoptosis [89].…”